1. Identification of CD8+T cell PRDM1 in high-risk human plaques and its regulatory role in murine lesion development
- Author
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Han Jin, Maas, S. L., Chang Lu, Nagenborg, J., Manca, M., Joël Karel, Rachel Cavill, Olivia Waring, Sikkink, C. J. J. M., Barend Mees, Daemen, M. J. A. P., Evgueni Smirnov, Judith Sluimer, Emiel van der Vorst, Erik Biessen, RS: Carim - B07 The vulnerable plaque: makers and markers, Pathologie, RS: FSE DACS, Dept. of Advanced Computing Sciences, RS: FSE DACS Mathematics Centre Maastricht, MUMC+: MA Vaatchirurgie CVC (3), Vascular Surgery, RS: Carim - V03 Regenerative and reconstructive medicine vascular disease, and MUMC+: MA Med Staf Spec Vaatchirurgie (9)
- Subjects
Physiology ,Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fritz Thyssen Stiftung T cells have a prominent role in the pathogenesis of atherosclerosis, although their function in atherosclerotic plaques is only partly understood. In this study, we utilize the advantages of high-throughput techniques and data analytic strategies to compare the inherent biological changes of T cells during plaque transition from a stable, non-haemorrhaged (low-risk) to a rupture-prone, haemorrhaged (high-risk) phenotype. We classified 43 human carotid arterial lesions into high- and low-risk plaques based on the presence/absence of intraplaque hemorrhages. RNA from these lesions was isolated and microarray gene expression data was obtained and analyzed by Weighted Gene Co-expression Network Analysis. A strong T cell signalling signature was identified in high- versus low-risk plaques, influencing angiogenesis and interferon-related processes. Bayesian network inference, cell type deconvolution and single-cell RNA sequencing analysis revealed that the T cell-associated gene program was linked to effector-memory cytotoxic, CD8+ T cells. This gene program appeared driven by CD8+ T cell-related transcription factors, including RUNX3, IRF7 and most importantly PRDM1. To validate these findings, we demonstrated in a murine model that T cell PRDM1 plays a key role in plaque formation, as atherosclerotic mice with a T cell specific Prdm1 deficiency developed larger and more advanced atherosclerotic plaques compared to control mice. In conclusion, our study unveils a clear PRDM1-regulated effector-memory cytotoxic CD8+ T cell footprint in plaque development and the shift from low- to high-risk plaques, thereby revealing CD8+ T cells and PRMD1 as potential targets for intervention in adverse T cell responses in human atherosclerotic lesions.
- Published
- 2022